The acute respiratory distress syndrome

Abstract

The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.

Figures

Figure 1. Chest radiograph of a patient with influenza-related pneumonia that illustrates early ALI, which progressed over 48 hours to more classic ALI that required positive-pressure ventilation.

(A) Anterior-posterior portable chest radiograph of a previously healthy 41-year-old man who presented to the emergency department with a 2-day history of myalgias and fever, a productive cough, and shortness of breath. Chest auscultation revealed rales and rhonchi posteriorly in both lung fields. The chest radiograph demonstrates patchy infiltrates in the right lower lung field and also in the left lower lung field. (B) Anterior-posterior chest radiograph 48 hours after the chest radiograph in A, 1 hour after endotracheal intubation (arrow) and initiation of positive-pressure ventilation using the ARDS Network lung-protective ventilation protocol (97). There was marked progression of the bilateral radiographic infiltrates, with dense consolidation in the right upper, right lower, and left lower lung zones. The patient’s hypoxemia steadily worsened during the 48 hours following his initial presentation, accompanied by an increase in respiratory rate to 40 breaths/minute. Diagnostic evaluation confirmed H1N1 influenza infection. All cultures for bacteria were negative. Recent clinical investigation indicates that it is possible in some patients to diagnose ALI in an early phase (9), as shown in A, well before the progression of acute respiratory failure to the need for mechanical ventilation, as illustrated in B. Earlier diagnosis of ALI could facilitate testing of therapeutic strategies that may have time-dependent efficacy prior to the development of established ALI that requires intubation and mechanical ventilation.

Figure 2. Mortality in ALI and ARDS.

Shown is the 60-day mortality reported over the last 11 years in randomized clinical trials from the ARDS Network. ARMA-12 refers to the mortality rate of 431 patients enrolled into the higher–tidal volume arm (12 ml tidal volume/kg predicted body weight), and ARMA-6 refers to the mortality of 430 patients enrolled in the lower–tidal volume arm (6 ml tidal volume/kg predicted body weight) of one study (97). FACTT fluid conservative refers to the mortality of the 500 patients enrolled into the fluid-conservative arm of the Fluid and Catheter Treatment Trial (120). ALTA and OMEGA refer to the combined mortalities of the 2 most recent trials (N = 517 in both trials combined), Albuterol for the Treatment of ALI (136) and Omega-3 Fatty Acid, Gamma-Linolenic Acid, and Antioxidant Supplementation in the Management of ALI or ARDS (138).

Figure 3. Molecular targets for new therapies that can lead to endothelial and epithelial barrier stabilization and reversal of increased permeability.

(A) Disrupted alveolar barrier function, resulting in increased permeability to water, proteins, and other solutes, is a hallmark of clinical and experimental ALI. Intra-alveolar accumulation of neutrophils, other leukocytes, and erythrocytes is also associated with altered endothelial and epithelial barrier function. TNF-α, IL-1, thrombin, and microbes and their toxins — including LPS, noxious agents, and factors generated by neutrophils and platelet-leukocyte interactions — can destabilize and disrupt alveolar barrier function, leading to increased permeability. (B) Disruption of VE-cadherin bonds is a central mechanism of altered endothelial barrier function in experimental ALI and in models of sepsis and systemic vascular destabilization. VE-cadherin is an endothelial-specific adherens junction protein that mediates Ca2+-dependent homophilic interactions at the lateral cell membranes of adjacent endothelial cells. VE-cadherin is regulated by cytoplasmic associations with catenins and actin and by cytoskeletal organization, in addition to intracellular signaling by Rho and Rac. Disruption of VE-cadherin bonds also facilitates transendothelial migration of leukocytes and, in some studies, is associated with accumulation of leukocytes and platelets in microvessels. (C) Stabilizing agonists (i) or small-molecule mimetics bind to stabilizing receptors (ii) on endothelial cells in alveolar and systemic vessels, restoring barrier integrity. Stabilizing agonists include S1P, Slit2N, Ang1, atrial natriuretic peptide, APC, and ATP; multiple intracellular pathways and mechanisms are implicated (iii) (reviewed in refs. 58, 61, 64). These intracellular mechanisms favorably influence cytoskeletal architecture, preserve catenin–VE-cadherin cytoplasmic interactions, prevent VE-cadherin internalization, and/or promote adherens junction formation (iv and v).

Figure 4. Resolution of ALI requires removal of alveolar edema fluid, removal of the acute inflammatory cells, and repair of the injured alveolar epithelium.

(A) Alveolar edema fluid reabsorption is driven by vectorial transport of sodium and chloride from the airspaces to the lung interstitium, creating a mini–osmotic gradient. Sodium is transported across apical sodium channels (including epithelial sodium channel [ENaC]) and then extruded basolaterally by sodium-potassium ATPase (NaKATPase). Chloride is transported by transcellular or paracellular pathways. In the presence of endogenous or exogenous cAMP stimulation, the rate of alveolar fluid transport increases substantially, accomplished by increased expression and activity of ENaC, NaKATPase, and opening of the CFTR. For net fluid clearance to occur, however, there needs to be a reasonably intact alveolar epithelial barrier (see C). AQP5, aquaporin 5. (B) The resolution of inflammation in ALI and ARDS requires the removal of neutrophils from the distal airspace of the lung. Neutrophils are normally taken up by alveolar macrophages, a process termed efferocytosis. The rate of neutrophil clearance can be accelerated by regulatory T lymphocytes, in part by release of TGF-β. (C) Restoration of the alveolar epithelial barrier initially occurs by reepithelialization of the epithelial surface by alveolar type II cells. Although it was previously thought that this occurred via proliferation of resident type II cells, new work suggests there may be niches of progenitor cells that also contribute. An α6β4+ progenitor cell has been identified in the mouse lung that is responsible for restoration of the alveolar epithelial barrier after bleomycin-induced lung injury (88). Thus, repair may occur by endogenous stem cell proliferation, not just by epithelial cell migration and proliferation of existing differentiated cells.

Figure 5. Mechanisms of ventilator-associated lung injury (VALI).

(A) ALI leads to lung endothelial and epithelial injury, increased permeability of the alveolar-capillary barrier, flooding of the airspace with protein-rich pulmonary edema fluid, activation of alveolar macrophages with release of proinflammatory chemokines and cytokines, enhanced neutrophil migration and activation, and fibrin deposition (hyaline membranes). (B) If the injured lung is ventilated with high tidal volumes and high inflation pressures (high-stretch ventilation), then lung injury is exacerbated, with increased lung endothelial and epithelial injury and/or necrosis, enhanced neutrophil margination, release of injurious neutrophil products such as proteases and oxidants, increased release of proinflammatory cytokines from alveolar macrophages and the lung epithelium, increased fibrin deposition, and increased hyaline membrane formation. Injurious mechanical ventilation can also impair alveolar fluid clearance (AFC) mechanisms. (C) In contrast, a protective ventilatory strategy (low-stretch ventilation) can limit further lung endothelial and epithelial injury, reduce the release of proinflammatory cytokines, and enhance alveolar fluid clearance through the active transport of sodium and chloride across the alveolar epithelium (see Figure 4), thereby reducing the quantity of pulmonary edema and allowing endothelial and epithelial repair to occur. Epithelial repair occurs through migration, proliferation, and differentiation of alveolar epithelial type II cells to repopulate the denuded basement membrane. Acute inflammation resolves through apoptosis of neutrophils, which are phagocytosed by alveolar macrophages (see Figure 4).